During vascular development a primitive vascular plexus differentiates into a diverse network of arteries, veins and capillaries. Concurrent with vascular differentiation is the onset of circulating blood pumped by the heart and the generation of hemodynamic forces that vary with vessel type. Although these processes are temporally linked, the extent to which vascular differentiation and genetic responses to hemodynamic forces are connected is unknown. Lung Kruppel-Like Factor (LKLF, KLF2) is a transcription factor required for cardiovascular development. LKLF mRNA expression in endothelial cells is rapidly induced by pulsatile shear stress and during development and in adult life LKLF is expressed in endothelial cells in proportion to their predicted exposure to fluid shear forces. Although LKLF expression is restricted to the endothelium, LKLF-deficient animals experience non-endothelial cardiovascular defects. Using conditional LKLF mice we have found that LKLF is required non-autonomously during cardiovascular development. These studies suggest that LKLF regulates paracrine cardiovascular signals by which endothelial cells direct the formation and function of the cardiovascular system. In the present proposal we will determine the cell types involved in this paracrine signaling pathway, the identity of the paracrine signals regulated by LKLF, and the role these signals play in mediating flow-dependent responses in mature animals. Understanding the mechanism by which LKLF regulates genetic responses in the developing and mature vasculature is expected to provide new insights into the pathogenesis and treatment of human vascular diseases.